Activating pyruvate dehydrogenase (PDH) complex. PDH converts pyruvate to acetyl CoA, which can then enter the TCA cycle upon condensation with oxaloacetate (OA) to form citrate. Insulin increases PDH activity through Akt kinase activation of PDH phosphatase, which in turn dephosphorylates and activates PDH (reaction 6D).
5.
Increasing synthesis of intrahepatic TG. During the digestive phase, some acetyl CoA is transferred from the mitochondria to the cytosol in the form of citrate, which is then converted back to acetyl CoA and oxaloacetate by the cytosolic enzyme ATP-citrate lyase (reaction 8D). Insulin increases ATP-citrate lyase gene expression through transcription factor SREBP1C. Once in the cytoplasm, acetyl CoA can enter fatty acid synthesis. The first step involves conversion of acetyl CoA to malonyl CoA by the enzyme acetyl-CoA carboxylase (reaction 9D). Insulin stimulates acetyl-CoA carboxylase gene expression through the transcription factor SREBP1C. Insulin also promotes dephosphorylation of acetyl-CoA carboxylase, which activates the enzyme. Malonyl CoA is converted to the 16-carbon fatty acid palmitoyl CoA by repetitive additions of acetyl groups (contributed by malonyl CoA) by the fatty acid synthase (FASN) complex (reaction 10D). FASN gene expression is enhanced by insulin through the transcription factor SREBP1C. Insulin also stimulates palmitoyl-CoA desaturase, which produces unsaturated fatty acids, and glycerol phosphate–fatty acyl transferases that esterify FFAs to G3P to form intrahepatic TG.
Palmitate synthesis requires the coenzyme NADPH. A major source of NADPH is the pentose phosphate pathway (PPP; see
Fig. 39.12 ). The first reaction converts G6P to 6-phosphogluconolactone by the enzyme glucose-6-phosphate dehydrogenase (G6PD; reaction 4D). Insulin increases G6PD gene expression through the transcription factor SREBP1C.
By activating steps that lead to generation of malonyl CoA, insulin indirectly inhibits oxidation of FFAs. Malonyl CoA inhibits the activity of CPT-I, which transports FFAs from the cytosol into the mitochondria (reaction 12D). As a result, FFAs that are synthesized by DNL cannot be transported into mitochondria, where they undergo β-oxidation (reaction 13F). Thus increased malonyl CoA prevents the futile cycle of FFA synthesis to FFA oxidation.
FFAs are converted to TGs by the liver (reaction 11D) and are either stored in the liver or transported to adipose tissue and muscle in the form of VLDL (see later). Insulin acutely promotes degradation of the VLDL apoprotein apoB-100. This keeps the liver from secreting VLDL during a meal when the blood is rich with chylomicrons. Thus the lipid made in response to insulin during a meal is released as VLDL during the interdigestive and fasting phases and provides an important source of energy to skeletal and cardiac muscle.